Clinical Significance of NOTCH1 and NOTCH2 Expression in Gastric Carcinomas: An Immunohistochemical Study

Lukas Bauer,Alexander Novotny,Alexander Hapfelmeier,Gisela Keller,Katja Ott,Axel Walch,Julia Slotta-Huspenina,Rupert Langer,Karen Becker,Agnes Takacs

doi:10.3389/fonc.2015.00094

Abstract

NOTCH signaling can exert oncogenic or tumor suppressive functions and can contribute to chemotherapy resistance in cancer. In this study, we aimed to clarify the clinicopathological significance and the prognostic and predictive value of NOTCH1 and NOTCH2 expression in gastric cancer (GC). NOTCH1 and NOTCH2 expression was determined immunohistochemically in 142 primarily resected GCs using tissue microarrays and in 84 pretherapeutic biopsies from patients treated by neoadjuvant chemotherapy. The results were correlated with survival, response to therapy, and clinico-pathological features. Primarily resected patients with NOTCH1-negative tumors demonstrated worse survival. High NOTCH1 expression was associated with early-stage tumors and with significantly increased survival in this subgroup. Higher NOTCH2 expression was associated with early-stage and intestinal-type tumors and with better survival in the subgroup of intestinal-type tumors. In pretherapeutic biopsies, higher NOTCH1 and NOTCH2 expression was more frequent in non-responding patients, but these differences were statistically not significant. Our findings suggested that, in particular, NOTCH1 expression indicated good prognosis in GC. The close relationship of high NOTCH1 and NOTCH2 expression with early tumor stages may indicate a tumor-suppressive role of NOTCH signaling in GC. The role of NOTCH1 and NOTCH2 in neoadjuvantly treated GC is limited.

Highlights

The NOTCH signaling cascade is a highly conserved signaling pathway, with a crucial role in developmental processes and differentiation programs in various tissues
NOTCH1 has been reported to be a marker of poor prognosis, and increased expression of the NOTCH intracellular domain (NICD) was associated with the presence of lymph node metastasis and worse survival [8, 9]
We demonstrated the prognostic relevance of NOTCH2 gene expression in residual tumor cells after chemotherapy of neoadjuvantly treated gastric cancer (GC) patients

Summary

Introduction

The NOTCH signaling cascade is a highly conserved signaling pathway, with a crucial role in developmental processes and differentiation programs in various tissues. Aberrant NOTCH signaling has been implicated in carcinogenesis in various organs, and oncogenic, as well as tumor-suppressive functions, have been described [1, 2]. NOTCH expression in gastric carcinomas evidence that NOTCH signaling contributes essentially to a drugresistant phenotype of tumor cells [3]. Different and partly opposite roles in one tumor entity have been found for NOTCH1 and NOTCH2, indicating specific functions of the two receptors [4]. In gastric cancer (GC), NOTCH1 and NOTCH2 are believed to contribute to tumor progression [5,6,7]. NOTCH signaling can exert oncogenic or tumor suppressive functions and can contribute to chemotherapy resistance in cancer. We aimed to clarify the clinicopathological significance and the prognostic and predictive value of NOTCH1 and NOTCH2 expression in gastric cancer (GC)

Objectives

Methods

Results

Conclusion